This invention relates generally to novel lactam metalloprotease inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloprotease), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor-xcex1 (TNF-xcex1) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF-xcex1 has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-xcex1 has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-xcex1 with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105), non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF-xcex1 are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MP-mediated tissue degradation, compounds which inhibit both MPs and TNF production may also have a particular advantage in diseases where both mechanisms are involved.
There are several patents that disclose hydroxamate and carboxylate based MP inhibitors.
WO95/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production. 
European Patent Application Publication No. 574,758 A1, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula: 
GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MPs as inhibitors of TNF production.
The compounds of the current invention act as inhibitors of MPs, in particular aggrecanase and TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Accordingly, one object of the present invention is to provide novel lactams that are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel lactams for use in therapy.
It is another object of the present invention to provide the use of novel lactams for the manufacture of a medicament for the treatment of an inflammatory disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula I: 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, R3, R3a, R3b, and R3c are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CH2CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94NHRa, xe2x80x94N(OH)COR5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SO2NHRa, S(xe2x95x90NH)2Ra, PO(OH)2, and PO(OH)NHRa;
ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds;
R1 is Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Ua13 Xaxe2x80x94Yaxe2x80x94Za;
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Y is absent or selected from O, NRa, S(O)p, and C(O);
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from O, NRa, S(O)p, and C(O);
Za is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rxe2x80x2, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
alternatively, R1 and R2 combine to form a C3-13 carbocyclic residue substituted with R1xe2x80x2 and 0-3 Rb or a 5-14 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with R1xe2x80x2 and 0-3 Rb;
Q is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R1xe2x80x2 is Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
R3 is selected from H, C1-6 alkyl, and (3-10 membered carbocyclic or heterocyclic ring)(CRRxe2x80x2)rxe2x80x94, wherein the 3-10 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-3 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
R3a is selected from H, C1-6 alkyl, phenyl, and benzyl;
R3b is selected from H, C1-6 alkyl, and (3-10 membered carbocyclic or heterocyclic ring)(CRRxe2x80x2)rxe2x80x94, wherein the 3-10 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-3 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
R3c is selected from H, C1-6 alkyl, phenyl, and benzyl;
alternatively one of R3, R3a, R3b, and R3c maybe independently selected from (CRRxe2x80x2)rxe2x80x2ORa, (CRRxe2x80x2)rxe2x80x2NRaRaxe2x80x2, (CRRxe2x80x2)rC(O)Ra, (CRRxe2x80x2)rC(O)ORa, (CRRxe2x80x2)rC(O)NRaRaxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)pRa, and (CRRxe2x80x2)rxe2x80x2S(O)pNRaRaxe2x80x2, provided that in the group (CRRxe2x80x2)rxe2x80x2S(O)pRa, Ra is other than H;
alternatively, R3 and R3b together with the carbon atoms to which they are attached combine to form a 3-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
alternatively, R3 and R3a together with the carbon atom to which they are attached combine to form a 3-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
alternatively, R3b and R3c together with the carbon atom to which they are attached combine to form a 3-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x3, at each occurrence, is independently selected from H, C1-4 alkyl, benzyl, C3-7 carbocyclic group, or a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring comprising 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, (CRRxe2x80x2)sO(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sS(O)p(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sNRa(CRRxe2x80x2)sxe2x80x2Rd, phenyl, and a 5-14 membered heterocyclic group comprising 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, phenyl, and a 5-6 membered heterocyclic group comprising 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, when two Rds are attached to adjacent atoms on R3, R3a, R3b, or R3c, they combine to form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring comprising 1-4 heteroatoms selected from the group consisting of NRa, O, and S;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is independently selected from phenyl substituted with 0-3 Rb, biphenyl substituted with 0-2 Rb, naphthyl substituted with 0-3 Rb and a 5-10 membered heteroaryl system comprising 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, xe2x80x94CH(R8)OC(xe2x95x90O)OR9, and 
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Re, C3-8 cycloalkyl substituted with 1-2 Re, and phenyl substituted with 0-2 Rb;
Re, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
s, at each occurrence, is selected from 0, 1, 2, and 3; and,
sxe2x80x2, at each occurrence, is selected from 0, 1, 2, and 3.
[2] In a preferred embodiment, the present invention provides compounds, wherein:
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-6 membered cyclic amide containing from 0-3 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds;
R1 is Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), S(O)p, and S(O)pNRa;
X is absent or selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene;
Y is absent or selected from O, NRa, and C(O);
Z is absent or selected from a C3-10 carbocyclic residue substituted with 0-5 Rb and a 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), S(O)p, and S(O)pNRa;
Xa is absent or selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene;
Ya is absent or selected from O, NRa, and C(O);
Za is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, and CHxe2x95x90CH2;
Rxe2x80x2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
alternatively, R1 and R2 combine to form a C3-10 carbocyclic residue substituted with R1xe2x80x2 and 0-3 Rb or a 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with R1xe2x80x2 and 0-3 Rb;
Q is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rb and a 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R1xe2x80x2 is Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
R3 is selected from H, C1-6 alkyl, and (5-10 membered carbocyclic or heterocyclic ring)(CRRxe2x80x2)rxe2x80x94, wherein the 5-10 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-3 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
R3a is selected from H, C1-6 alkyl, phenyl, and benzyl;
R3b is selected from H, C1-6 alkyl, and (5-10 membered carbocyclic or heterocyclic ring) (CRRxe2x80x2)rxe2x80x94, wherein the 5-10 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-3 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
R3c is selected from H, C1-6 alkyl, phenyl, and benzyl;
alternatively one of R3, R3a, R3b, and R3c maybe independently selected from (CRRxe2x80x2)rxe2x80x2ORa, (CRRxe2x80x2)rxe2x80x2NRaRaxe2x80x2, (CRRxe2x80x2)rC(O)Ra, (CRRxe2x80x2)rC(O)ORa, (CRRxe2x80x2)rC(O)NRaRaxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)pRa, and (CRRxe2x80x2)rxe2x80x2S(O)rxe2x80x2NRaRaxe2x80x2, provided that in the group (CRRxe2x80x2)rxe2x80x2S(O)pRa, Ra is other than H;
alternatively, R3 and R3b together with the carbon atoms to which they are attached combine to form a 4-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
alternatively, R3 and R3a together with the carbon atom to which they are attached combine to form a 4-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
alternatively, R3b and R3c together with the carbon atom to which they are attached combine to form a 4-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, (CRRxe2x80x2)sO(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sS(O)p(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sNRa(CRRxe2x80x2)sxe2x80x2Rd, phenyl, and a 5-10 membered heterocyclic group comprising 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, phenyl, and a 5-6 membered heterocyclic group comprising 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, when two Rds are attached to adjacent atoms on R3, R3a, R3b, or R3c, they combine to form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring comprising 1-4 heteroatoms selected from the group consisting of NRa, O, and S;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, 3, and 4;
s, at each occurrence, is selected from 0, 1, and 2; and,
sxe2x80x2, at each occurrence, is selected from 0, 1, and 2.
[3] In another preferred embodiment, the present invention provides compounds, wherein:
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
ring B is a 5-6 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds;
R1 is Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
U is absent or is selected from: O, NRa, C(O), C(O)NRa, and S(O)p;
X is absent or is C1-4 alkylene;
Y is absent or selected from O and NRa;
Z is absent or selected from a C5-6 carbocyclic residue substituted with 0-3 Rb and a 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)NRa, and S(O)p;
Xa is absent or selected from C1-6 alkylene and C2-6 alkenylene;
Ya is absent or selected from O and NRa;
Za is selected from H, a C5-10 carbocyclic residue substituted with 0-3 Rc and a 5-10 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rc;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Q;
R, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rxe2x80x2, at each occurrence, is independently selected from H and CH3;
alternatively, R1 and R2 combine to form a C5-6 carbocyclic residue substituted with R1xe2x80x2 and 0-3 Rb or a 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with R1xe2x80x2 and 0-3 Rb;
Q is selected from H, a C5-6 carbocyclic residue substituted with 0-5 Rb and a 5-6 membered heterocyclic system comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R1xe2x80x2 is Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
R3 is selected from H, C1-6 alkyl, and (5-6 membered carbocyclic or heterocyclic ring) (CH2)rxe2x80x94, wherein the 5-6 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
R3a is selected from H, C1-6 alkyl, phenyl, and benzyl;
R3b is selected from H, C1-6 alkyl, and (5-6 membered carbocyclic or heterocyclic ring) (CH2)rxe2x80x94, wherein the 5-6 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an, Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
R3c is selected from H, C1-6 alkyl, phenyl, and benzyl;
alternatively one of R3, R3a, R3b, and R3c is independently selected from (CRRxe2x80x2)rxe2x80x2ORa, (CRRxe2x80x2)rxe2x80x2NRaRaxe2x80x2, (CRRxe2x80x2)rC(O)Ra, (CRRxe2x80x2)rC(O)ORa, (CRRxe2x80x2)rC(O)NRaRaxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)pRa, and (CRRxe2x80x2)rxe2x80x2S(O)pNRaRaxe2x80x2, provided that in the group (CRRxe2x80x2)rxe2x80x2S(O)pRa, Ra is other than H;
alternatively, R3 and R3b together with the carbon atoms to which they are attached combine to form a 4-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
alternatively, R3 and R3a together with the carbon atom to which they are attached combine to form a 5-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
alternatively, R3b and R3c together with the carbon atom to which they are attached combine to form a 5-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd, provided that the cyclic moiety contains other than an Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, and phenyl;
r, at each occurrence, is selected from 0, 1, 2, and 3; and,
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, and 3.
[4] In another preferred embodiment, the present invention provides compounds, wherein:
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
ring B is a 5 membered cyclic amide containing from 0-1 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds;
R1 is Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za;
U is absent;
X is absent;
Y is absent;
Z is absent or selected from phenyl substituted with 0-2 Rb and a 5-6 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or selected from C1-4 alkylene and C2-4 alkenylene;
Ya is absent or is O;
Za is selected from H, a C6-10 aryl residue substituted with 0-3 Rc and a 5-10 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rc;
R2 is selected from C1-6 alkylene, (CRRxe2x80x2)rxe2x80x2OH, and (CRRxe2x80x2)rxe2x80x2NRaH;
R3 is selected from H, C1-6 alkyl, and (5-6 membered carbocyclic or heterocyclic ring) (CH2)rxe2x80x94, wherein the 5-6 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-1 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd;
R3a is selected from H, C1-6 alkyl, phenyl, and benzyl;
R3b is selected from H, C1-6 alkyl, and (5-6 membered carbocyclic or heterocyclic ring) (CH2)rxe2x80x94 wherein the 5-6 membered carbocyclic or heterocyclic ring comprises carbon atoms and 0-1 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd;
R3c is selected from H, C1-6 alkyl, phenyl, and benzyl;
alternatively, R3 and R3b together with the carbon atoms to which they are attached combine to form a 4, 5, 6, 7 or 8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-1 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd;
alternatively, R3 and R3a together with the carbon atom to which they are attached combine to form a 5-6 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-1 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd;
alternatively, R3b and R3c together with the carbon atom to which they are attached combine to form a 5-6 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-1 ring heteroatoms selected from O, N, NRa, and S(O)p and substituted with 0-2 Rd;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and phenyl;
r, at each occurrence, is selected from 0, 1, and 2; and,
rxe2x80x2, at each occurrence, is selected from 0, 1, and 2.
[5] In another preferred embodiment, the present invention provides compounds, wherein:
(1S-cis)-2-[3-amino-3-[4-[2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]-N-hydroxycyclohexanecarboxamide bis(trifluoroacetate) (salt);
(1R-trans)-2-[3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]-N-hydroxycyclohexanecarboxamide bis(trifluoroacetate) (salt);
(1R-trans)-2-[3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]cyclohexanecarboxylic acid bis(trifluoroacetate) (salt);
(1S-cis)-2-[(3S)-3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]cyclopentanecarboxylic acid bis(trifluoroacetate) (salt);
(1S-cis)-2-[(3S)-3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]-N-hydroxycyclopentanecarboxamide bis(trifluoroacetate) (salt);
(1R-trans)-2-[(3S)-3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]-N-hydroxycyclopentanecarboxamide bis(trifluoroacetate) (salt);
(1S-cis)-2-[(3S)-3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]-N-hydroxy-4,4-dimethylcyclopentanecarboxamide bis(trifluoroacetate) (salt);
(1S-cis)-1-[(3S)-3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]-2,3-dihydro-N-hydroxy-1H-indene-2-carboxamide bis(trifluoroacetate) (salt);
(3R-trans)-4-[(3S)-3-amino-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinyl]tetrahydro-N-hydroxy-3-furancarboxamide bis(trifluoroacetate) (salt);
(xcex2R)-3-amino-N-hydroxy-xcex2-(2-methylpropyl)-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinepropanamide bis(trifluoroacetate) (salt);
(xcex2R)-3-amino-xcex2-(2-methylpropyl)-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinepropanoic acid bis(trifluoroacetate) (salt); and,
3-amino-N-hydroxy-xcex1,xcex1-dimethyl-3-[4-[(2-methyl-4-quinolinyl) methoxy]phenyl]-2-oxo-1-pyrrolidinepropanamide bis(trifluoroacetate) (salt);
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as acute infection, acute phase response, age related macular degeneration, alcoholism, anorexia, asthma, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
In another embodiment, the present invention provides novel lactams for use in therapy.
In another embodiment, the present invention provides the use of novel lactams for the manufacture of a medicament for the treatment of an inflammatory disorder.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic groupxe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that the heterocycle contains other than an Nxe2x80x94O, Nxe2x80x94S, Oxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94S bond. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benztriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5xe2x80x2-triiodothyronine, and 3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc. . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of xcex3-lactams of formula 10 are prepared by the methods outlined in Schemes 1 and 2. R1-substituted methyl acetate 1 is deprotonated to form the enolate using bases such as sodium bis(trimethylsilyl)amide, lithium N,N-diisopropylamide, and sodium hydride. Alkylation with R2xe2x80x94X provides 2. Further alkylation with allyl bromide under similar basic conditions gives ester 3. The olefin in 3 is then cleaved by ozonolysis or by dihydroxylation (OsO4/NMO) followed by diol cleavage (NaIO4) to give aldehyde 4. Treatment of the aldehyde 4 and the appropriately substituted xcex2-amino acid 5 with zinc in acetic acid at elevated temperature leads to reductive amination and lactamization to give xcex3-lactam 7. The xcex3-lactamization gives a mixture of two diastereomers epimeric at the quaternary center. The diastereomers of 7 are either separated or taken to the next step as a mixture.
Alternatively, aldehyde 4 is converted to lactam 7 through a stepwise sequence. Condensation of 4 with the xcex2-amino ester 5 through reductive amination provides secondary amine 6. The reductive amination can be affected with reagents such as sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. Amine 6 is converted to 7 via thermally induced lactamization or methyl ester hydrolysis followed by amide bond formation using reagents such as BOP.
Lactam 7 can also be prepared from ester 3 through the carboxylic acid 8. Acid 8 and xcex2-amino ester 5 can be coupled using standard peptide coupling reagents well known in the literature such as DCC, BOP, and TBTU (Bodanszky, M. in Peptide Chemistry A Practical Textbook, 2nd ed. Springer-Verlag, New York, 1993). Olefin degradation (O3/PPh3, or OsO4/NaIO4) and deoxygenation (Et3SiH/CF3COOH) gives lactam 7. 
Many of the xcex2-amino acid derivatives 5 are commercially available or are prepared from the commercial material by simple protecting group manipulations. Alternatively the xcex2-amino acids can be prepared by a variety of methods discussed in xe2x80x9cEntioselective Synthesis of xcex2-Amino Acidsxe2x80x9d editied by Eusebio Juraisti, Wiley-VCH publisher. Others are synthesized by methods outlined in Scheme Ia. The cyano acetate compound 301 may be reacted with reagents such as LDA to generate the enolate which may be alkylated with an electrophile such as an alkyl halide or tosylate to give intermediate 302. The nitrile can be reduced with reagents such as LAH or Raney nickel or hygrogenation over PtO2 to give the xcex2-amino acid 303.
Alternatively the xcex2-amino acid like compound 307 can be prepared starting with a protected ester like Evans oxazolidinone. Generating the enolate with bases like LDA and reacting this with a bromoacetate to give compounds like 305. Hydrolysis of the oxazolidinone will give the carboxylic acid 306 and this can be transformed into the amine by a Curtius like reaction.
xcex2-amino acids can also be prepared from the starting ketoester compound 308, reacting this with an amine like benzyl anime to prepare the enamine 309. The enamine can be reduced by a number of methods like hygrogenation over Pd/C or stepwise with sodium triacetoxyborohydride to give the saturated intermediate and then hydrogenation with Pd/C to prepare compounds like 310. Alternatively, the xcex2-amino acid 310 can be prepared by reacting the xcex1-xcex2 unsaturated ester in a Michael like fashion with an amine like benzyl amine or azide to give the amine compound 312. The compound 312 can be reduced by hydrogenation conditions well known in the literature to give compound 310.
These reactions can be carried out in such a way as to prepare enantiospecfic xcex2-amino acids (G. Bartoli, C. Cimarelli, E. Marcantoni, G. Palmieri, M. Petrini, J. Org. Chem. 1994, 59, 5328-5335 and C. Cimerilli, G. Palmieri, J. Org. Chem. 1996, 61, 5557-5563.) or the isomers may be separated by chiral column HPLC. 
The methyl ester of 7 (R11=Me) is converted to hydroxamic acid 10 by treatment with hydroxylamine under basic conditions (KOH or NaOMe) in methanol (Scheme 2) The methyl ester 7 (R11=Me) can also be converted to benzyl protected hydroxamic acid with O-benzylhydroxylamine using Weinreb""s trimethylalluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp""s bis[bis(trimethylsilyl)amido]tin reagent (Wang, W. -B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). Hydrogenolysis then provides the hydroxamic acid 10. Alternatively, 10 can be prepared through the carboxylic intermediate 11. Carboxylic acid 11 is converted to 10 via coupling with hydroxylamine or NH2OBn followed by deprotection. 
A variety of ethers of 4-hydroxyphenyllactam 13 are prepared using intermediate 7 when R1 is benzyloxyphenyl group (Scheme 3). Removal of benzyl protecting group followed by alkylation with R4xe2x80x94X produces 13. The alkylation can be affected with bases such as K2CO3, Cs2CO3, NaH, and t-BuOK. Alternatively compounds like 13 can also be prepared with R4OH under Mitsunobu conditions.
R4 can be appended to the aromatic ring of compound 12 by converting the phenol to the aryl triflate with methods like triflic anhydride and DIEA in an appropriate solvent. The aryl triflate is reacted with an organometallic under Stille or Suzuki conditions in the presence of palladium(0) catalyst to give compound 200. Alternatively, compound 12 reacts with lower or higher-order cuprates to give compound 200 as well.
Compounds like 201 can be prepared by reacting the phenol compound 12 with acyl halides or isocyantes in appropriate solvents and temperatures. The biaryl ethers compound 202 can be prepared by treating compound 12 with aryl boronic acids in the presence of a copper catalyst.
Compounds of Scheme 3 can be converted to their corresponding hydroxamic acids following the methods outlined in Scheme 2. 
Another series of phenyllactams of formula 15 is prepared following the sequence outlined in Scheme 4. Starting from 7 when R1 is phenyl methyl group, radical bromination with N-bromosuccinimide gives bromide 14. Alkylation of 14 with R4xe2x80x94OH or R4xe2x80x94NH2 under basic conditions gives 15a and 15b respectively. Ester 15 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
Another series of phenyl lactams of Formula 10 like those described in Scheme 5 can be prepared from compound 7 where R1 is nitrophenyl. The nitro group can be reduced to the aniline compound 210 by methods well known in the literature. The amine compound 211 can be prepared by reaction of compound 210 with an appropriately substituted aldehyde to give the imine that can be reduced by reagents such as sodium borohydride or sodium triacetoxyborohydride. Alternatively, the aniline compound 210 can be reacted with an appropriately substituted compound containing a leaving group like bromide or tosylate to give amine compound 211.
The sulfonamide compound 212 can be prepared by reaction of the aniline 210 with a substituted sulfonylchloride by methods well known in the literature. The amide compound 213 can be prepared by reacting the aniline 210 with an acid chloride or carboxylic acid with a coupling reagent used to make amide bonds previously described. The urea or carbamate compound 213 can be prepared from reacting the aniline 210 with an appropriately substituted isocyanate or chloroformate respectively. The compounds of Scheme 5 can be converted to their corresponding hydroxamic acids by methods described in Scheme 2. 
A variety of heterocyclic substituted lactams are prepared from 7 when R1 is carbobenzyloxy group. As a representative example, scheme 6 illustrates the synthesis of the benzimidazole series. Following hydrogenolysis of 7, the resultant acid 18 is coupled with diamine 19 with coupling reagents such as BOPxe2x80x94Cl. Upon heating of 20 in acetic acid, benzimidazole 21 is formed. Ester 21 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
A series of isoxazole-substituted lactams of formula 26 is prepared using common intermediate 18 following the sequence outlined in Scheme 7. The carboxylic acid 18 is converted to aldehyde 23 by hydroboration and Swern oxidation. Oxime formation, in situ oxidation and [3+2] dipolar cycloaddition with acetylene 25 provides isoxazole 26. Ester 26 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
Another series of lactams of formula 30 with an oxadiazole substituent at the xcex1 position is prepared using common intermediate 18 following the sequence outlined in Scheme 8. Acid 18 is first coupled with hydrazine to give 27. Condensation with aldehyde 28 and oxidative cyclization with PhI(OAc)2 provided oxadiazole 30 (Yang, R. Y.; Dai, L. X. J. Org. Chem. 1993, 58, 3381). Ester 30 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
Another series of lactams of formula 38 with an aminothiazole substituent at the xcex1 position is prepared following the sequence outlined in Scheme 9. Consecutive alkylations with bromoacetaldehyde dimethyl acetal and R2xe2x80x94X gives 33. Reaction of 33 with xcex2-amino acid 5 using zinc in acetic acid provides lactam 34. Bromoketone 36 is obtained from 34 by Wacker oxidation and bromination. Treatment of bromoketone 36 with thiourea produces aminothiazole 37 (Markees, D. G.; Burger, A. J. Am. Chem. Soc. 1948, 70, 3329). Alkylation with R4xe2x80x94X then provides 38. Ester 38 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
Another series of lactams of formula 42 with an imidazole substituent at the xcex1 position is prepared following the sequence outlined in Scheme 10. Consecutive alkylations with bromoacetaldehyde dimethyl acetal and R2xe2x80x94X gives 41. Reaction of 41 with xcex2-amino acid 5 using zinc in acetic acid provides lactam 42. Ester 42 is converted to the hydroxamic acid following the sequences outlined in Sceme 2. 
A series of succinimides of formula 45 is prepared from intermediate 4 (Scheme 11). The synthesis entails oxidation to carboxylic acid 43, coupling with xcex2-amino acid 5, and succinimide formation. Ester 45 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
A variety of compounds of formula I wherein R2 is NHR can be prepared by methods described in Scheme 12. The hydroxyglycine acid was converted to the methyl ester using methanol and HCl to give compound 51, which was converted to the N-Boc protected amino acid 52 by methods described in the literature. The benzyloxyphenylglcine compound 53 was prepared by reacting the phenol compound 52 with benzyl bromide in acetone with a base such as potassium carbonate. The 2-allyl phenyl acetic acid compound 54, was prepared by treating compound 53 with LDA (2 eq) and allyl bromide. The olefin compound 54 is oxidized to the aldehyde compound 55 using ozone and triphenylphosphine, then reacted with an appropriate amine to give the imine, which can be reduced with reagents similar to sodium triacetoxyborohydride, to give the amine compound 56. The xcex3-lactam compound 57 is prepared by heating the amine compound 56 in an appropriate solvent such as toluene. The benzyl ether is removed by methods well known in the literature such as hydrogenation using palladium on carbon in hydrogen, to give compound 58. The compound 59 is prepared by reacting the phenol 58 with an appropriately substituted halide or the like in acetone with a base such as potassium carbonate. The hydroxamic acid compound 61 was prepared from compound 59 by methods well known in the literature for removing N-Boc groups and conversion of the methyl ester previously described. Alternatively the amine compound 60 can be treated with appropriately substituted acid chloride, isocyanate, carboxylic acid with coupling agents such as carbonyldiimidazole or the like, that are well known in the literature for making amide bonds. Alternatively the amine of compound 60 can be converted to an isocyanate by a variety of methods known in the literature like using phosgene and a base such as sodium carbonate, and reacting this with an appropriately substituted amine, to give compound 62. The hydroxamic acid was prepared by methods previously described. 
A variety of compounds of formula I wherein the lactam is a six member ring can be prepared by methods described in Scheme 13. The ester compound 64 is converted to the acid compound 65 by methods well known in the literature, such as lithium hydroxide in methanol water, then coupled to an appropriately substituted amine by methods well described in the literature for making amide bonds, such as TBTU and N-methyl morpholine in DMF, to give compound 66. The hydroxy compound 67 was prepared from the olefin compound 66 by reduction with 9-BBN and oxidative workup with hydrogen peroxide. The xcex4-lactam 69 is prepared by converting the hydroxy of compound 67 to a leaving group by methods well known in the literature such as carbon tetrabromide and triphenylphosphine in methylene chloride. The bromide compound 68 was reacted with a base such as sodium hydride in THF to give the xcex4-lactam 69. The hydroxamic acid compound 70 was prepared by methods previously described. 
A variety of compounds of formula I wherein the lactam is a four member ring can be prepared by methods described in Scheme 14. The ester compound 71 was converted to the acid compound 72 and coupled to an appropriately substituted amine by methods well known in the literature and previously described. The xcex2-lactam 75 is prepared by converting the hydroxy of compound 73 to a leaving group by methods well known in the literature, such as methanesulfonyl chloride and potassium carbonate in pyridine. The methanesulfonate compound 74 was reacted with a base such as potassium carbonate in acetone to give the xcex2-lactam 75. The hydroxamic acid compound 77 was prepared by methods previously described. 
A variety of compounds of formula I wherein the lactam is replaced with a hydantoin ring can be prepared by methods described in Scheme 15. The amine compound 78 was prepared from the N-Boc compound 54 by methods previously described for the removal of Boc protecting groups. The urea compound 79 was prepared by converting the amine compound 78 to an isocyanate by methods well known in the literature and previously described, such as triphosgene and DIEA in methylene chloride and reacting this with an appropriately substituted amine. Alternatively, the amine 78 can be reacted with an isocyanate that is commercially available or can be prepared as described above. The hydantoin compound 80 was prepared by reacting the urea compound 79 with potassium carbonate in acetone. The final hydroxamic acid compound 81 was prepared by methods well documented previously. 
A variety of compounds of formula I wherein the lactam is replaced with a imidazolinone can be prepared by methods described in Scheme 16. Compound 84 was prepared from the phenylglycine compound 82, by hydrolysis to the acid and coupling to an appropriately substituted amine as well described in the literature and previously detailed. The N-Boc group is removed by conventional methods previously described to give the amine compound 85. The heterocyclic compound 86 was prepared by reacting the amine compound 85 with paraformaldehyde in toluene at elevated temperatures. The final hydroxamic acid compound 87 was prepared by methods well documented previously. 
A variety of compounds of formula I wherein R2 is CH2NHR can be prepared by methods described in Scheme 17. The cyanoacetate compound 89 was prepared by reacting the hydroxyphenylacetonitrile with benzyl bromide in acetone with potassium carbonate to give compound 88, which was in turn reacted with sodium ethoxide and diethylcarbonate in toluene at elevated temperatures. The allyl cyanoacetate compound 90 was prepared from the cyanoacetate compound 89 by generating the anion with a base such as sodium hydride and reacting this with allyl bromide in DMF. The nitrile lactam compound 94 was prepared by a sequence of steps previously described in several other Schemes. The Nxe2x80x94Boc methyleneamine compound 96 was prepared by reduction of the nitrile lactam compound 94, using palladium on carbon with HCl in methanol, to give the amino compound 95 which was then protected by conventional methods with a Boc group to give compound 96. The final hydroxamic acid compounds 99 and 101 were prepared by methods previously described. 
A variety of compounds of formula I wherein R2 is CH2OH can be prepared by methods described in Scheme 18. The allyl compound 104 was prepared from hydroxyphenyl acetate, by reaction with benzyl bromide and potassium carbonate in acetone as previously described and then treating the benzyloxy phenyl acetate compound 103 with LDA and allyl bromide in THF. The methylene hydroxy compound 105 was prepared by treating the benzyloxy phenyl acetate compound 104 with paraformaldehyde and sodium methoxide in DMSO. The hydrolysis of the ester and coupling of the carboxylic acid to an appropriately substituted amine was described earlier to give the compound 107. The protected O-silyl compound 108 was prepared by methods well described in the literature, then oxidation to the aldehyde compound 109 with ozone was described previously. The lactam compound 110 was prepared from the aldehyde compound 109 by treatment with triethylsilane and TFA in methylene chloride at ambient temperatures. The final hydroxamic acid compound 112 was prepared by methods previously described. 
A variety of compounds of formula I wherein R1 is a heterocycle, such as thiophene, can be prepared by methods described in Scheme 19. The thiophene substituted compound 115 was prepared by treating the thiophene acetate compound 113 with LDA and allyl bromide to give compound 114, and subsequently with LDA and methyl iodide in THF. The thiophene compound 117 was prepared by methods previously detailed for ester hydrolysis to the acid and coupling the carboxylic acid to an amine. The oxidation of the olefin compound 117, to the aldehyde compound 118, was performed by the action of osmium tetraoxide and NMMO, to give the diol, then treatment with NaIO4. The formation of the lactam ring compound 119 was previously described using triethylsilane and TFA in methylene chloride. The aldehyde thiophene compound 120 was prepared by chemistry well described in the literature, using phosphorus oxychloride in DMF. The aldehyde compound 120 was reacted with sodium borohydride in methanol to give alcohol compound 121 that was reacted with carbon tetrabromide and triphenyl phosphine to give the bromide compound 122. The bromide was treated with phenol and potassium carbonate in acetone to give the phenyl ether compound 123. The final hydroxamic acid compound 124 was prepared by methods previously described. 
Another series of lactams of formula 135 is prepared following the sequence outlined in Scheme 20. Ester 124 is alkylated with t-butyl bromoacetate to give 126. Ester 126 is converted to 132 following previously described sequence. Removal of t-butyl group and coupling with NH2Rxe2x80x2 under literature well known conditions gives 134. Ester 134 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
One diasteriomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. Lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.